X-ray contrast media containing a chemical compound as the active pharmaceutical ingredient(s) having two triiodinated phenyl groups linked by a linking group are usually referred to as dimeric contrast agents or dimers. During the years a wide variety of iodinated dimers have been proposed. Currently, one contrast medium having an iodinated non-ionic dimer as the active pharmaceutical ingredient is on the market, the product Visipaque™ containing the compound (contrast agent) Iodixanol.

In WO2009/008734 of the applicant a novel dimeric contrast agent named Ioforminol is disclosed. The properties of this is described in more detail in the publications Chai et al. “Predicting cardiotoxicity propensity of the novel iodinated contrast medium GE-145: ventricular fibrillation during left coronary arteriography in pigs”, Acta Radiol, 2010, and in Wistrand, L. G., et al “GE-145, a new low-osmolar dimeric radiographic contrast medium”, Acta Radiol, 2010. Ioforminol (GE-145) is named Compound 1 herein and has the following structure:
5,5′-(2-Hydroxypropane-1,3-diyl)bis(formylazanediyl)bis(N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide).
The manufacture of non-ionic X-ray contrast media involves the production of the chemical drug, the active pharmaceutical ingredient (API), i.e. the contrast agent, followed by the formulation into the drug product, herein denoted the X-ray composition or contrast media.
WO2006/016815 of the applicant provides an overview of possible synthetic routes to prepare Iodixanol. As shown in scheme I of this Iodixanol can be prepared from, or via, 5-amino-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (Compound B), which is commercially available. The free amino group of this is then acylated to provide an acetyl group and the hydroxyl groups in the substituents may also be protected by acylation. In at last step the final intermediate 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (also called “Compound A”) is reacted with a bis-alkylation agent such as epichlorohydrin to yield the dimeric contrast agent Iodixanol. Similarly, WO2009/008734 of the applicant provides a synthetic route for preparing the contrast agent Ioforminol. This agent may also be synthesized from 5-amino-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (Compound B). The free amino group of the isophthalamide compound is then acylated to provide a formyl group and the hydroxyl groups in the substituents may also be protected by acylation. The protecting groups may be removed for example by hydrolysis to give N1,N3-bis(2,3-dihydroxypropyl)-5-formylamino-2,4,6-triiodoisophthalamide and this is reacted with a bis-alkylation agent such as epichlorohydrin to yield the dimeric contrast agent Ioforminol.
Following completion of the synthetic steps preparing a dimeric contrast agent as described above, the crude product comprising the contrast agent needs purification to provide acceptable drug product purity. For a commercial drug product, it is important for the primary production to be efficient and economical and to provide a drug substance fulfilling the regulatory specifications, such as those mandated by the US Pharmacopeia. In addition, the cost of the secondary production depends on the cost of the primary production of the contrast agent, which is directly linked to the efficiency of the synthesis and purification processes in the primary production.
It is therefore critical to optimize each process in the primary production of the contrast agent. For both compounds, Ioforminol and Iodixanol, the best identified synthetic routes involve going from a monomeric molecule to the dimeric molecule in the last step of the syntheses, and it has been identified that the main impurities in the crude products are monomeric compounds and salts. Particularly for Ioforminol the crude Ioforminol product from the syntheses include about 2-10% monomeric impurities, which need to be removed.
The purity of the crude iodixanol product is typically 75-90%, such as only 83-84%, which means that the purification effect needs to be very good to yield a product within the quality requirements. At the same time iodixanol is produced in large quantities, so the yield in the process is very important in terms of financial performance.
Several methods have been described to purify crude products, such as crude X-ray products. U.S. Pat. No. 5,811,581 provides a process for purifying contrast agents using a chromatographic column. The use of liquid chromatography is a disadvantage in industrial processes in particular due to the high costs involved. A more feasible purification method has been found to be crystallization, such as e.g. described in WO2006/016815. However, there are challenges with purifications by crystallization also, such as the long time and the large volume equipment needed, and a disadvantage is especially the loss of yield during the process involving incomplete precipitation before filtration and washing. Crystallizations also have the drawback of high energy consumption as they will typically include reflux of organic solvents and recovery of such. US2001/0021828 of the applicant relates to Iodixanol and to a method of recovering intermediate 5-acetamido-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound A) from the desalinated and desolventized dimerisation reaction mixture. That invention comprises a method using ultrafiltration prior to the crystallisation of Iodixanol to recover non-crystalline Compound A. U.S. Pat. No. 5,221,485 discloses the use of nano filtration as an alternative or substitute method for the purification of a crude diagnostic agent, such as an X-ray contrast agent. Particularly, a method of purifying crude Ioversol, a monomeric compound, by removing small molecular weight process impurities such as ethylene glycol and dimethylsulfoxide using reverse osmosis is disclosed. The problem to be solved by the present invention may be regarded as the provision of an alternative purification procedure for crude dimeric X-ray contrast agents, avoiding chromatography and crystallization, and wherein monomeric impurities are removed.